Male Testosterone Responsible for Sex Differences in ACL Injuries?

Elizabeth Hofheinz, M.P.H., M.Ed. • Thu, September 29th, 2016

Lab rats at Johns Hopkins are pointing the way toward new information on the sex differences in anterior cruciate ligament (ACL) debate. Scientists have found that testosterone in males may explain why women are up to 10x more likely than men to injure their ACL. Specifically, said the September 20, 2016 news release, “they found that normal male rats with natural supplies of testosterone had stronger ACLs than those that had been castrated and no longer produced the hormone…”

“The primary implication of the study is that testosterone may contribute to the ACL’s ability to withstand tensile loads and may be one of multiple factors response for the disparate ACL injury rate between men and women, ” says William Romani, Ph.D., M.H.A., a physical therapist and sports medicine researcher who was a visiting faculty member in The Johns Hopkins University’s Department of Biomedical Engineering from 2009 to 2015. Romani now works with the AARP Foundation’s Experience Corps.

As indicated in the news release, senior study author Jennifer Elisseeff, Ph.D., a biomedical engineer at The Johns Hopkins University, says the new finding could eventually lead to techniques that use circulating sex hormone levels to identify athletes at higher risk for ACL injury who may benefit from training strategies to strengthen the ligament.

Dr. Romani told OTW, “In my practice working with college athletes I recognized the disparities in ACL injury rates between male and female athletes. Our early work in young women identified an association between ACL strength and sex hormone levels near ovulation, suggesting that estradiol was related to ligament strength in women. The remodeling and strength of many collagen rich connective tissues is modulated by estrogens and androgens. We identified that the human ACL had the receptors for androgens like testosterone. The thought was that where estrogen may be detrimental to ligament strength in women resulting in more ACL injuries, testosterone may make the ligament stronger and result in fewer injuries in men. The next step was determining if testosterone impacted the ACL so we used our animal model in the current study to determine that higher levels of circulating testosterone in male rats were, in fact, related to stronger ligaments.”

Asked about her initial thoughts on which pathways and molecules testosterone and estrogen act through to influence ligament strength, Dr. Romani told OTW, “In our 2010 paper in the Journal of the National Athletic Training Association we saw a relationship between estradiol and Type I and III mRNA [messenger ribonucleic acid] expression suggesting that the sex hormones impact the cascade of collagen remodeling through RNA then protein expression. However, sex hormones also act through Sex Hormone Binding Globulin and in the case of tissue remodeling, matrix metalloproteinases [MMPs]. Hashimi and Slauterbeck have started to look at this mechanism previously and it has been identified in other collagen rich tissue. We suspect that the sex hormone mediated activation and proliferation of these MMPs may be present in ACL tissue and is the subject of ongoing investigation.”

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Does Gender Play a Role in ACL Reconstruction Outcome?

Sophie Bodek • Wed, August 6th, 2014

The anterior cruciate ligament (ACL) is one of the most frequently injured knee ligaments with an injury incidence of over 200, 000 cases per year, according to the University of California, San Francisco Department of Orthopedic Surgery's website. By the numbers, more ACL injuries happen to men because a greater amount of men participate in sports. Women, however, have a higher risk of ACL injury due to lower extremity alignment, looseness in the joints, hormonal differences, and ACL size. According to National Collegiate Athletic Association (NCAA) statistics, women are 2 to 8 times more likely to experience an ACL injury from sports participation. Although it is well documented that women are more likely to sustain an ACL injury, several doctors wondered if females are predisposed to poor outcomes following ACL reconstruction.

John Ryan, M.D.; Robert A. Magnussen, M.D.; Charles L. Cox, M.D., M.P.H.; Jason G. Hurbanek, M.D.; David C. Flanigan, M.D.; and Christopher C. Kaeding, M.D. conducted a systematic review of the medical literature concerning the outcomes of ACL reconstruction by sex. Published in the March issue of The Journal of Bone and Joint Surgery, the review is titled, "ACL Reconstruction: Do Outcomes Differ by Sex?" The doctors evaluated a total of 13 studies in order to determine whether sex played a role in the outcome of ACL reconstruction. After reviewing the studies, determining several outcome measures, and assessing the results for homogeneity, the doctors performed a meta-analysis. The four outcome measures analyzed were "graft failure risk, contralateral ACL injury risk, knee laxity, and patient-reported outcome scores following ACL reconstruction." They determined homogeneity with a chi-square test and performed the meta-analysis using a Mantel-Haenszel analysis with a random-effects model.

After analyzing each outcome measure, the doctors found no difference in "graft failure risk, contralateral ACL rupture risk, or postoperative knee laxity on physical examination." The doctors did not find a clinically important difference in patient-reported outcomes. Seven studies evaluated graft rupture risk. Although the risk was 4.6% for men and 5.4% for women, the doctors found no difference after performing the meta-analysis. Three studies reported on contralateral ACL rupture; the risk for men was 4.0% and 7.4% for women.

Female Shape Responsible for ACL Tears

Biloine W. Young • Tue, September 10th, 2013

Women are two to eight times more likely than men to suffer a debilitating tear of the anterior cruciate ligament (ACL) in the knee. So what is going on with women? A new study suggests that a combination of body type and the way women land may be to blame.

In two new studies published in the Journal of Athletic Training, Marc Norcross of Oregon State University, documents how women who performed a series of jumping exercises landed (more often than did men) in a way associated with elevated risk of ACL injuries.

Both men and women tended to land stiffly, which can lead to ACL injuries, but women were 3.6 times more likely to land in a "knock-kneed" position. It is this position that the researchers believe may be the critical factor leading to the gender disparity in ACL tears.

"We found that both men and women seem to be using their quad region the same, so that could not explain why females are more at risk, " Norcross said. "Using motion analysis, we were able to pinpoint that this inability to control the frontal-plane knee loading—basically stress on the knee from landing in a knock-kneed position—as a factor more common in women.”

"Future research may isolate why women tend to land this way, " he added, "but it could be because of basic biology. Women have wider hips, making it more likely that their knees come together after jumping."

The researchers used motion analysis software to monitor the landing strategies of 82 physically active men and women. They found that both males and females had an equal likelihood of landing stiffly—likely from tensing the muscles in their quads before landing—putting them at higher risk of ACL tears. Women, however, were more likely to land in a "knee valgus" position, essentially knock-kneed.

"You see ACL injuries in any sport where you have a lot of jump stops and cuts, so basketball, soccer, lacrosse, and volleyball are high-risk sports, " said Norcross. "We know that people who hurt themselves tend to look stiff when they land and that the combined 'knee loading' from multiple directions is likely causing the injury event.” Norcross notes that ACL injuries can lead to early onset arthritis, which then impacts an athletes’ ability to stay physically active.

Women 3X More Likely to Rupture ACL

Elizabeth Hofheinz, M.P.H., M.Ed. • Wed, January 9th, 2013

A team of Yale researchers has published a review article indicating that female athletes are three times more likely than their male counterparts to suffer from anterior cruciate ligament (ACL) ruptures. The article, which appears in the January 2013 issue of the Journal of the American Academy of Orthopaedic Surgeons (JAAOS), discusses recent research focusing on the unique anatomical differences in the female knee that may contribute to higher injury rates.

“As female athletes have increased their participation in sports, many studies have shown the vulnerability of female athletes to ACL ruptures, ” said Karen Sutton, M.D., in the January 8, 2013 news release. Dr. Sutton is assistant professor at Yale University Department of Orthopaedics and Rehabilitation, and is lead author of the article. “This devastating injury has a long recovery period and a slow return to sport. Thus, research has been done focusing on why women are more vulnerable to ACL injuries and how to prevent them.”

A slew of research studies have found that preseason and ongoing neuromuscular training programs as part of an overall sports training program aimed specifically at improving knee stability when jumping, landing or pivoting can significantly decrease ACL injury risk among girls and women. Unique anatomical features of female athletes such as a larger quadriceps angle (“Q angle”)—the angle at which the femur meets the tibia—may cause a greater pull of the knee muscles during physical activity, and contribute to more ACL injuries among females.

Anatomical differences in the female knee should be taken into consideration during ACL reconstruction, said Dr. Sutton. Females are more likely than males to have a smaller, A-shaped intercondylar notch, making ACL reconstruction more challenging, and possibly requiring altered surgical techniques.

“All female athletes, starting in adolescence, should learn appropriate training techniques, ” said Dr. Sutton. “This includes the appropriate way to land from a jump, increasing the strength of muscles that could have a protective affect on the ACL—core, gluteal, quadriceps and hamstring muscles, as well as working on the body’s reaction to change of direction and change of speed.”

Birth Control Pills Decrease Likelihood of Knee Injuries

Elizabeth Hofheinz, M.P.H., M.Ed. • Sat, March 26th, 2016

Young women who take birth control pills are less likely to have serious knee injuries, says new research from The University of Texas Medical Branch at Galveston. The study is published in Medicine & Science in Sports & Exercise.

As indicated in the March 18, 2016 news release, “Using a national insurance claims and prescription database of 23, 428 young women between 15 and 19, the study found that women with an ACL [anterior cruciate ligament] knee injury who were taking the birth control pill were less likely to need corrective surgery than women of the same age with ACL injuries who do not use the birth control pill. Researchers have proposed that the female hormone estrogen makes women more vulnerable to ACL injury by weakening this ligament. A previous investigation found that more ACL injuries in women occur during the points of their menstrual cycle when estrogen levels are high.”

"Birth control pills help maintain lower and more consistent levels of estrogen, which may prevent periodic ACL weakness, " said lead author and M.D., Ph.D. student Aaron Gray. "With this in mind, we examined whether oral contraceptive use protected against ACL injuries that require surgery in women."

Women between15-19 years old in need of ACL reconstructive surgery, the age group with the highest rates of ACL injuries by a wide margin, were 22% less likely to be using the birth control pill than non-injured women of the same age.

Gray told OTW, “I had previously been working on a biomechanics investigation to determine whether specific athletic maneuvers might predispose women to ACL injury more so than men. During this study, my literature search revealed that a large portion of the excessive ACL injuries in women might be occurring due to the presence of estrogen. Many previous studies have shown that the ACL is weaker during the first two weeks of the menstrual cycle when estrogen is present. It is also known that oral contraceptives, as a consequence, reduce estrogen levels or help to maintain a constant level of estrogen. It was biologically plausible that their use could potentially prevent these injuries.

New Study: Autografts Last Longer for ACL Reconstruction

Sophie Bodek • Wed, July 16th, 2014

Anterior cruciate ligament (ACL) injuries occur about 200, 000 times each year and about 100, 000 of those patients undergo reconstructive surgery.

Seventy percent of ACL injuries occur when patients participate in agility sports, mainly basketball, soccer, skiing, and football. ACL injuries are more prevalent in patients 15-45 years old since people in this age group are more likely to maintain an active lifestyle. Women are more likely to suffer an ACL injury although greater numbers of men become injured since men are more likely to participate in sports.

On July 11, 2014, researchers presented the results of a new study regarding the use of autografts for reconstructing ligaments. The data was presented at the American Orthopedic Society of Sports Medicine's Annual Meeting (AOSSM). Lead author, Dr. Craig R. Bottoni, from Tripler Army Medical Center in Honolulu, revealed that when reconstructing ligaments, allografts fail more frequently than autografts.

Bottoni followed 99 patients who’d had an ACL reconstructed either from an allograft, tissue from a donor, or an autograft, tissue taken from the same individual. Bottoni and his team followed these patients for 10 years and found that 80% of grafts remained intact and stabile.

Although the majority of grafts remained in good condition, patients with an allograft experienced a failure rate that was more than three times higher than those reconstructed with an autograft.

All allografts were from the same tissue bank and processed in the same fashion, the grafts were fixed identically in all knees, and all patients followed the same postoperative recovery procedure.

Since the study only examined a tibialis posterior allograft, the authors cautioned that it would be premature to draw conclusions about other types of allografts. Out of 99 individuals studied, 95 were in active military duty and 87 were male. There were 13 allograft failures and 4 autograft failures in the group that required revision reconstruction. Between the remaining allograft and autograft patients, there was no difference in mean Tegner, SANE, or IKDC scores.